Omeprazole (omeprazole 40 mg)
- Human Prescription
-
Archived
-
IMPRINT: ANDRX 640 40 MG
SHAPE: capsule
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1 Indications And Usage
1.1 Duodenal Ulcer (adults)
Omeprazole delayed-release capsules USP are indicated for
short-term treatment of active duodenal ulcer in adults. Most patients heal
within four weeks. Some patients may require an additional four weeks of
therapy.
Omeprazole delayed-release capsules USP in combination with clarithromycin
and amoxicillin, is indicated for treatment of patients with
H. pylori infection and duodenal ulcer disease (active or
up to 1-year history) to eradicate
H. pylori in
adults.
Omeprazole delayed-release capsules USP in combination with clarithromycin is
indicated for treatment of patients with
H. pylori
infection and duodenal ulcer disease to eradicate
H.
pylori in adults.
Eradication of
H. pylori has been shown to reduce
the risk of duodenal ulcer recurrence [
see Clinical Studies
(14.1) and Dosage and Administration (2)].
Among patients who fail therapy, Omeprazole delayed-release capsules USP with
clarithromycin is more likely to be associated with the development of
clarithromycin resistance as compared with triple therapy. In patients who fail
therapy, susceptibility testing should be done. If resistance to clarithromycin
is demonstrated or susceptibility testing is not possible, alternative
antimicrobial therapy should be instituted. [
See
Microbiology section (12.4)], and the clarithromycin
package insert, Microbiology section.)
1.2 Gastric Ulcer (adults)
Omeprazole delayed-release capsules USP are indicated for
short-term treatment (4 to 8 weeks) of active benign gastric ulcer in adults.
[
See Clinical Studies (14.2)]
1.3 Treatment of Gastroesophageal Reflux Disease
(GERD) (adults and pediatric patients)
Symptomatic GERD
Omeprazole delayed-release capsules USP are indicated for the treatment of
heartburn and other symptoms associated with GERD in pediatric patients and
adults.
Erosive Esophagitis
Omeprazole delayed-release capsules USP are indicated for the short-term
treatment (4 to 8 weeks) of erosive esophagitis that has been diagnosed by
endoscopy in pediatric patients and adults. [
See Clinical
Studies (14.4)]
The efficacy of omeprazole delayed-release capsules USP used for longer than
8 weeks in these patients has not been established. If a patient does not
respond to 8 weeks of treatment, an additional 4 weeks of treatment may be
given. If there is recurrence of erosive esophagitis or GERD symptoms (eg,
heartburn), additional 4 to 8 week courses of omeprazole may be
considered.
1.4 Maintenance of Healing of Erosive Esophagitis
(adults and pediatric patients)
Omeprazole delayed-release capsules USP are indicated to maintain
healing of erosive esophagitis in pediatric patients and adults.
Controlled studies do not extend beyond 12 months. [
See
Clinical Studies (14.4)]
1.5 Pathological Hypersecretory Conditions
(adults)
Omeprazole delayed-release capsules USP are indicated for the
long-term treatment of pathological hypersecretory conditions (eg,
Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic
mastocytosis) in adults.
2 Dosage And Administration
Omeprazole delayed-release capsules USP should be taken before
eating. In the clinical trials, antacids were used concomitantly with omeprazole
delayed-release capsules USP.
Patients should be informed that the omeprazole delayed-release capsules USP
should be swallowed whole.
For patients unable to swallow an intact capsule, alternative administration
options are available [
See Dosage and Administration (2.8)].
2.1 Short-Term Treatment of Active Duodenal
Ulcer
The recommended adult oral dose of omeprazole delayed-release
capsules USP is 20 mg once daily. Most patients heal within four weeks. Some
patients may require an additional four weeks of therapy.
2.2
H. pylori Eradication
for the Reduction of the Risk of Duodenal Ulcer Recurrence
Triple Therapy (Omeprazole delayed-release
capsules USP /clarithromycin/amoxicillin) — The recommended adult oral
regimen is omeprazole delayed-release capsules USP 20 mg plus clarithromycin 500
mg plus amoxicillin 1000 mg each given twice daily for 10 days. In patients with
an ulcer present at the time of initiation of therapy, an additional 18 days of
omeprazole delayed-release capsules USP 20 mg once daily is recommended for
ulcer healing and symptom relief.
Dual Therapy (Omeprazole delayed-release
capsules USP /clarithromycin) — The recommended adult oral regimen is
omeprazole delayed-release capsules USP 40 mg once daily plus clarithromycin 500
mg three times daily for 14 days. In patients with an ulcer present at the time
of initiation of therapy, an additional 14 days of omeprazole delayed-release
capsules USP 20 mg once daily is recommended for ulcer healing and symptom
relief.
2.3 Gastric Ulcer
The recommended adult oral dose is 40 mg once daily for 4 to 8
weeks.
2.4 Gastroesophageal Reflux Disease (GERD)
The recommended adult oral dose for the treatment of patients
with symptomatic GERD and no esophageal lesions is 20 mg daily for up to 4
weeks. The recommended adult oral dose for the treatment of patients with
erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily for 4
to 8 weeks.
2.5 Maintenance of Healing of Erosive
Esophagitis
The recommended adult oral dose is 20 mg daily. [
See Clinical Studies (14.4)]
2.6 Pathological Hypersecretory Conditions
The dosage of omeprazole delayed-release capsules USP in patients
with pathological hypersecretory conditions varies with the individual patient.
The recommended adult oral starting dose is 60 mg once daily. Doses should be
adjusted to individual patient needs and should continue for as long as
clinically indicated. Doses up to 120 mg three times daily have been
administered. Daily dosages of greater than 80 mg should be administered in
divided doses. Some patients with Zollinger-Ellison syndrome have been treated
continuously with omeprazole delayed-release capsules USP for more than 5
years.
2.7 Pediatric Patients
For the treatment of GERD and maintenance of healing of erosive
esophagitis, the recommended daily dose for pediatric patients- 1 to 16 years of
age is as follows:
| Patient Weight |
Omeprazole Daily Dose |
| 5 < 10 kg |
5 mg |
| 10 < 20 kg |
10 mg |
| > 20 kg |
20 mg |
On a per kg basis, the doses of omeprazole required to heal erosive
esophagitis in pediatric patients are greater than those for adults.
Alternative administrative options can be used for pediatric patients unable
to swallow an intact capsule [
See Dosage and Administration
(2.8)].
2.8 Alternative Administration Options
Omeprazole is available as a delayed-release capsule USP.
For patients who have difficulty swallowing capsules, the contents of a
omeprazole delayed-release capsules USP can be added to applesauce. One
tablespoon of applesauce should be added to an empty bowl and the capsule should
be opened. All of the pellets inside the capsule should be carefully emptied on
the applesauce. The pellets should be mixed with the applesauce and then
swallowed immediately with a glass of cool water to ensure complete swallowing
of the pellets. The applesauce used should not be hot and should be soft enough
to be swallowed without chewing. The pellets should not be chewed or crushed.
The pellets/applesauce mixture should not be stored for future use.
3 Dosage Forms And Strengths
Omeprazole delayed-release capsules, 40 mg, are opaque, hard gelatin, dark
green and light green colored capsules, imprinted “Andrx 640” on the cap and “40
mg” on the body.
4 Contraindications
Omeprazole delayed-release capsules USP are contraindicated in
patients with known hypersensitivity to any component of the formulation.
Hypersensitivity reactions may include anaphylaxis, anaphylactic shock,
angioedema, bronchospasm, interstitial nephritis, and urticaria [
See Adverse Reactions ( 6
)].
5 Warnings And Precautions
5.1 Concomitant Gastric Malignancy
Symptomatic response to therapy with omeprazole does not preclude
the presence of gastric malignancy.
5.2 Atrophic Gastritis
Atrophic gastritis has been noted occasionally in gastric corpus
biopsies from patients treated long-term with omeprazole.
5.3 Combination Use of Omeprazole Delayed-release
Capsules USP with Amoxicillin
Serious and occasionally fatal hypersensitivity (anaphylactic)
reactions have been reported in patients on penicillin therapy. These reactions
are more likely to occur in individuals with a history of penicillin
hypersensitivity and/or a history of sensitivity to multiple allergens. Before
initiating therapy with amoxicillin, careful inquiry should be made concerning
previous hypersensitivity reactions to penicillins, cephalosporins or other
allergens. If an allergic reaction occurs, amoxicillin should be discontinued
and appropriate therapy instituted. Serious anaphylactic reactions require
immediate emergency treatment with epinephrine. Oxygen, intravenous steroids and
airway management, including intubation, should also be administered as
indicated.
Pseudomembranous colitis has been reported with nearly all antibacterial
agents and may range in severity from mild to life-threatening. Therefore, it is
important to consider this diagnosis in patients who present with diarrhea
subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and
may permit overgrowth of clostridia. Studies indicate that a toxin produced by
Clostridium difficile is a primary cause of
“antibiotic-associated colitis.”
After the diagnosis of pseudomembranous colitis has been established,
therapeutic measures should be initiated. Mild cases of pseudomembranous colitis
usually respond to discontinuation of the drug alone. In moderate to severe
cases, consideration should be given to management with fluids and electrolytes,
protein supplementation, and treatment with an antibacterial drug clinically
effective against
Clostridium difficile
colitis.
5.4 Combination Use of Omeprazole Delayed-release
Capsules USP with Clarithromycin
Clarithromycin should not be used in pregnant women except in
clinical circumstances where no alternative therapy is appropriate. If pregnancy
occurs while taking clarithromycin, the patient should be apprised of the
potential hazard to the fetus. (See Warnings in prescribing information for
clarithromycin.)
Co-administration of omeprazole and clarithromycin has resulted in increases
in plasma levels of omeprazole, clarithromycin, and 14-hydroxy-clarithromycin.
[
See Clinical Pharmacology (
12)
]
Concomitant administration of clarithromycin with cisapride or pimozide, is
contraindicated.
6 Adverse Reactions
6.1 Clinical Trials Experience with Omeprazole
Delayed-release Capsules USP Monotherapy
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in the clinical trials of a drug
cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice.
The safety data described below reflects exposure to omeprazole
delayed-release capsules USP in 3096 patients from worldwide clinical trials
(465 patients from US studies and 2,631 patients from international studies).
Indications clinically studied in US trials included duodenal ulcer, resistant
ulcer, and Zollinger-Ellison syndrome. The international clinical trials were
double blind and open-label in design. The most common adverse reactions
reported (i.e., with an incidence rate equal or greater than 2%) from omeprazole delayed-release
capsules USP-treated patients enrolled in these studies included headache
(6.9%), abdominal pain (5.2%), nausea (4.0%), diarrhea (3.7%), vomiting (3.2%),
and flatulence (2.7%).
Additional adverse reactions that were reported with an incidence equal or greater than1%
included acid regurgitation (1.9%), upper respiratory infection (1.9%),
constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia (1.3%), back pain
(1.1%), and cough (1.1%).
The clinical trial safety profile in patients greater than 65 years of age
was similar to that in patients 65 years of age or less.
The clinical trial safety profile in pediatric patients who received
omeprazole delayed-release capsules USP was similar to that in adult patients.
Unique to the pediatric population, however, adverse reactions of the
respiratory system were most frequently reported in both the 1 to less than 2 and 2 to
16 year age groups (75.0% and 18.5%, respectively). Similarly, fever was
frequently reported in the 1 to 2 year age group (33.0%), and accidental
injuries were reported frequently in the 2 to 16 year age group (3.8%).[
See Use in Specific Populations (8.4)]
6.2 Clinical Trials Experience with Omeprazole
Delayed-release Capsules USP in Combination Therapy for
H.
pylori Eradication
In clinical trials using either dual therapy with omeprazole
delayed-release capsules USP and clarithromycin, or triple therapy with
omeprazole delayed-release capsules USP, clarithromycin, and amoxicillin, no
adverse reactions unique to these drug combinations were observed. Adverse
reactions observed were limited to those previously reported with omeprazole,
clarithromycin, or amoxicillin alone.
Dual Therapy (Omeprazole delayed-release
capsules USP /clarithromycin)
Adverse reactions observed in controlled clinical trials using combination
therapy with omeprazole delayed-release capsules USP and clarithromycin (n =
346) that differed from those previously described for omeprazole
delayed-release capsules USP alone were taste perversion (15%), tongue
discoloration (2%), rhinitis (2%), pharyngitis (1%) and flu-syndrome (1%). (For
more information on clarithromycin, refer to the clarithromycin prescribing
information, Adverse Reactions section).
Triple Therapy (Omeprazole delayed-release
capsules USP /clarithromycin/amoxicillin)
The most frequent adverse reactions observed in clinical trials using
combination therapy with omeprazole delayed-release capsules USP,
clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion
(10%), and headache (7%). None of these occurred at a higher frequency than that
reported by patients taking antimicrobial agents alone. (For more information on
clarithromycin or amoxicillin, refer to the respective prescribing information,
Adverse Reactions sections).
6.3 Post-marketing Experience
The following adverse reactions have been identified during
post-approval use of omeprazole delayed-release capsules USP. Because these
reactions are voluntarily reported from a population of uncertain size, it is
not always possible to reliably estimate their actual frequency or establish a
causal relationship to drug exposure.
Body As a Whole: Hypersensitivity reactions
including anaphylaxis, anaphylactic shock, angioedema, bronchospasm,
interstitial nephritis, urticaria, (see also
Skin
below); fever; pain; fatigue; malaise;
Cardiovascular: Chest pain or angina, tachycardia,
bradycardia, palpitations, elevated blood pressure, peripheral edema
Endocrine: Gynecomastia
Gastrointestinal: Pancreatitis (some fatal),
anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal
atrophy of the tongue, stomatitis, abdominal swelling, dry mouth. During
treatment with omeprazole, gastric fundic gland polyps have been noted rarely.
These polyps are benign and appear to be reversible when treatment is
discontinued. Gastroduodenal carcinoids have been reported in patients with ZE
syndrome on long-term treatment with omeprazole. This finding is believed to be
a manifestation of the underlying condition, which is known to be associated
with such tumors.
Hepatic: Liver disease including hepatic failure
(some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular
disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver
function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]
Metabolic/Nutritional: Hypoglycemia, hyponatremia,
weight gain
Musculoskeletal: Muscle weakness, myalgia, muscle
cramps, joint pain, leg pain
Nervous System/Psychiatric: Psychiatric and sleep
disturbances including depression, agitation, aggression, hallucinations,
confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream
abnormalities; tremors, paresthesia; vertigo
Respiratory: Epistaxis, pharyngeal pain
Skin: Severe generalized skin reactions including
toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema
multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus;
petechiae; purpura; alopecia; dry skin; hyperhidrosis
Special Senses: Tinnitus, taste perversion
Ocular: Optic atrophy, anterior ischemic optic
neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision,
double vision
Urogenital: Interstitial nephritis, hematuria,
proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract
infection, glycosuria, urinary frequency, testicular pain
Hematologic: Agranulocytosis (some fatal),
hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leucocytosis
7 Drug Interactions
Drugs for which gastric pH can affect
bioavailability
Because of its profound and long lasting inhibition of gastric acid
secretion, it is theoretically possible that omeprazole may interfere with
absorption of drugs where gastric pH is an important determinant of their
bioavailability (e.g., ketoconazole, ampicillin esters, and iron salts). In the
clinical trials, antacids were used concomitantly with the administration of
omeprazole delayed-release capsules USP.
Drugs metabolized by cytochrome P450
(CYP)
Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin,
drugs that are metabolized by oxidation in the liver. There have been reports of
increased INR and prothrombin time in patients receiving proton pump inhibitors,
including omeprazole, and warfarin concomitantly. Increases in INR and
prothrombin time may lead to abnormal bleeding and even death. Patients treated
with proton pump inhibitors and warfarin may need to be monitored for increases
in INR and prothrombin time.
Although in normal subjects no interaction with theophylline or propranolol
was found, there have been clinical reports of interaction with other drugs
metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram,
benzodiazepines). Patients should be monitored to determine if it is necessary
to adjust the dosage of these drugs when taken concomitantly with omeprazole
delayed-release capsules USP.
Concomitant administration of omeprazole and voriconazole (a combined
inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the
omeprazole exposure. Dose adjustment of omeprazole is not normally required.
However, in patients with Zollinger-Ellison syndrome, who may require higher
doses up to 240 mg/day, dose adjustment may be considered. When voriconazole
(400 mg Q12h x 1 day, then 200 mg x 6 days) was given with omeprazole (40 mg
once daily x 7 days) to healthy subjects, it significantly increased the
steady-state C
max and AUC
0-24 of
omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3,
4.4) respectively as compared to when omeprazole was given without
voriconazole.
Antiretroviral Agents
Concomitant use of atazanavir and proton pump inhibitors is not recommended.
Co-administration of atazanavir with proton pump inhibitors is expected to
substantially decrease atazanavir plasma concentrations and thereby reduce its
therapeutic effect.
Omeprazole has been reported to interact with some antiretroviral drugs. The
clinical importance and the mechanisms behind these interactions are not always
known. Increased gastric pH during omeprazole treatment may change the
absorption of the antiretroviral drug. Other possible interaction mechanisms are
via CYP2C19. For some antiretroviral drugs, such as atazanavir and nelfinavir,
decreased serum levels have been reported when given together with omeprazole.
Following multiple doses of nelfinavir (1250 mg, bid) and omeprazole (40 mg,
qd), AUC was decreased by 36% and 92%, C
max by 37% and
89% and C
min by 39% and 75% respectively for nelfinavir
and M8. Following multiple doses of atazanavir (400 mg, qd) and omeprazole (40
mg, qd, 2 hr before atazanavir), AUC was decreased by 94%, C
max by 96%, and C
min by 95%. Concomitant
administration with omeprazole and drugs such as atazanavir and nelfinavir is
therefore not recommended. For other antiretroviral drugs, such as saquinavir,
elevated serum levels have been reported with an increase in AUC by 82%, in
C
max by 75% and in C
min by 106%
following multiple dosing of saquinavir/ritonavir (1000/100 mg) bid for 15 days
with omeprazole 40 mg qd co-administered days 11 to 15. Dose reduction of
saquinavir should be considered from the safety perspective for individual
patients. There are also some antiretroviral drugs of which unchanged serum
levels have been reported when given with omeprazole.
Tacrolimus
Concomitant administration of omeprazole and tacrolimus may increase the
serum levels of tacrolimus.
8 Use In Specific Populations
8.1 Pregnancy
Pregnancy Category C
Reproductive studies in rats and rabbits with omeprazole and multiple cohort
studies in pregnant women with omeprazole use during the first trimester do not
show an increased risk of congenital anomalies or adverse pregnancy outcomes.
There are no adequate and well-controlled studies on the use of omeprazole in
pregnant women. Because animal reproduction studies are not always predictive of
human response, this drug should be used during pregnancy only if clearly
needed. The vast majority of reported experience with omeprazole during human
pregnancy is first trimester exposure and the duration of use is rarely
specified, e.g., intermittent vs. chronic. An expert review of published data on
experiences with omeprazole use during pregnancy by TERIS – the Teratogen
Information System – concluded that therapeutic doses during pregnancy are
unlikely to pose a substantial teratogenic risk (the quantity and quality of
data were assessed as fair).
Three epidemiological studies compared the frequency of congenital
abnormalities among infants born to women who used omeprazole during pregnancy
with the frequency of abnormalities among infants of women exposed to H
2-receptor antagonists or other controls. A population-based
prospective cohort epidemiological study from the Swedish Medical Birth
Registry, covering approximately 99% of pregnancies, reported on 955 infants
(824 exposed during the first trimester with 39 of these exposed beyond first
trimester, and 131 exposed after the first trimester) whose mothers used
omeprazole during pregnancy.
In utero exposure to
omeprazole was not associated with increased risk of any malformation (odds
ratio 0.82, 95% CI 0.50 to 1.34), low birth weight or low Apgar score. The
number of infants born with ventricular septal defects and the number of
stillborn infants was slightly higher in the omeprazole-exposed infants than the
expected number in the normal population. The author concluded that both effects
may be random.
A retrospective cohort study reported on 689 pregnant women exposed to either
H
2-blockers or omeprazole in the first trimester (134
exposed to omeprazole). The overall malformation rate was 4.4% (95% CI 3.6 to
5.3) and the malformation rate for first trimester exposure to omeprazole was
3.6% (95% CI 1.5 to 8.1). The relative risk of malformations associated with
first trimester exposure to omeprazole compared with non-exposed women was 0.9
(95% CI 0.3 to 2.2). The study could effectively rule out a relative risk
greater than 2.5 for all malformations. Rates of preterm delivery or growth
retardation did not differ between the groups.
A controlled prospective observational study followed 113 women exposed to
omeprazole during pregnancy (89% first trimester exposures). The reported rates
of major congenital malformations was 4% for the omeprazole group, 2% for
controls exposed to non-teratogens, and 2.8% in disease-paired controls
(background incidence of major malformations 1 to 5%). Rates of spontaneous and
elective abortions, preterm deliveries, gestational age at delivery, and mean
birth weight did not differ between the groups. The sample size in this study
has 80% power to detect a 5-fold increase in the rate of major malformation.
Several studies have reported no apparent adverse short-term effects on the
infant when single dose oral or intravenous omeprazole was administered to over
200 pregnant women as premedication for cesarean section under general
anesthesia.
Reproductive studies conducted with omeprazole on rats at oral doses up to 56
times the human dose and in rabbits at doses up to 56 times the human dose did
not show any evidence of teratogenicity. In pregnant rabbits, omeprazole at
doses about 5.5 to 56 times the human dose produced dose-related increases in
embryo-lethality, fetal resorptions, and pregnancy loss. In rats treated with
omeprazole at doses about 5.6 to 56 times the human dose, dose-related
embryo/fetal toxicity and postnatal developmental toxicity occurred in
offspring. [
See Animal Toxicology and/or Pharmacology (13.2)].
8.3 Nursing Mothers
Omeprazole concentrations have been measured in breast milk of a
woman following oral administration of 20 mg. The peak concentration of
omeprazole in breast milk was less than 7% of the peak serum concentration. This
concentration would correspond to 0.004 mg of omeprazole in 200 mL of milk.
Because omeprazole is excreted in human milk, because of the potential for
serious adverse reactions in nursing infants from omeprazole, and because of the
potential for tumorigenicity shown for omeprazole in rat carcinogenicity
studies, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the
mother.
8.4 Pediatric Use
Use of omeprazole delayed-release capsules USP in pediatric and
adolescent patients 1 to 16 years of age for the treatment of GERD is supported
by a) extrapolation of results, already included in the currently approved
labeling, from adequate and well-controlled studies that supported the approval
of omeprazole delayed-release capsules USP for adults, and b) safety and
pharmacokinetic studies performed in pediatric and adolescent patients. [
See Clinical Pharmacology, Pharmacokinetics, Pediatric for
pharmacokinetic information
(12.3)
and
Dosage and Administration (2),
Adverse Reactions (6.1)
and
Clinical Studies, (14.6)]. The safety and
effectiveness of omeprazole delayed-release capsules USP for the treatment of
GERD in patients less than 1 year of age have not been established. The safety and
effectiveness of omeprazole delayed-release capsules USP for other pediatric
uses have not been established.
8.5 Geriatric Use
Omeprazole was administered to over 2000 elderly individuals (equal or greater than 65 years of age ) in clinical trials in the U.S. and Europe. There were no
differences in safety and effectiveness between the elderly and younger
subjects. Other reported clinical experience has not identified differences in
response between the elderly and younger subjects, but greater sensitivity of
some older individuals cannot be ruled out.
Pharmacokinetic studies have shown the elimination rate was somewhat
decreased in the elderly and bioavailability was increased. The plasma clearance
of omeprazole was 250 mL/min (about half that of young volunteers) and its
plasma half-life averaged one hour, about twice that of young healthy
volunteers. However, no dosage adjustment is necessary in the elderly. [
See Clinical Pharmacology (12.3)]
8.6 Hepatic Impairment
Consider dose reduction, particularly for maintenance of healing
of erosive esophagitis. [
See Clinical Pharmacology (12.3)]
8.7 Renal Impairment
No dosage reduction is necessary. [
See
Clinical Pharmacology (12.3)]
8.8 Asian Population
Consider dose reduction, particularly for maintenance of healing
of erosive esophagitis. [
See Clinical Pharmacology (12.3)]
10 Overdosage
Reports have been received of overdosage with omeprazole in
humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical
dose). Manifestations were variable, but included confusion, drowsiness, blurred
vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry
mouth, and other adverse reactions similar to those seen in normal clinical
experience. [
See Adverse Reactions ( 6
)] Symptoms were transient, and no serious clinical
outcome has been reported when omeprazole delayed-release capsules USP was taken
alone. No specific antidote for omeprazole overdosage is known. Omeprazole is
extensively protein bound and is, therefore, not readily dialyzable. In the
event of overdosage, treatment should be symptomatic and supportive.
As with the management of any overdose, the possibility of multiple drug
ingestion should be considered. For current information on treatment of any drug
overdose, contact a Poison Control Center at 1-800-222-1222.
Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were lethal to
mice, rats, and dogs, respectively. Animals given these doses showed sedation,
ptosis, tremors, convulsions, and decreased activity, body temperature, and
respiratory rate and increased depth of respiration.
11 Description
The active ingredient in Omeprazole Delayed-release Capsules USP
is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3,
5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1
H-benzimidazole, a compound that inhibits gastric acid
secretion. Its empirical formula is C
17H
19N
3O
3S, with a
molecular weight of 345.42. The structural formula is:
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Omeprazole is a white to off-white crystalline powder that melts with
decomposition at about 155°C. It is a weak base, freely soluble in ethanol and
methanol, and slightly soluble in acetone and isopropanol and very slightly
soluble in water. The stability of omeprazole is a function of pH; it is rapidly
degraded in acid media, but has acceptable stability under alkaline
conditions.
Omeprazole delayed-release capsules USP is supplied as delayed-release
capsules for oral administration. Each delayed-release capsule contains either
10 mg, 20 mg or 40 mg of omeprazole in the form of enteric-coated granules with
the following inactive ingredients: cetyl alcohol, disodium phosphate, hydroxy
propyl methylcellulose phthalate, lactose anhydrous, povidone, sodium lauryl
sulfate, sucrose and talc. The capsule shells and imprinting inks have the
following inactive ingredients: ammonium hydroxide, D and C Yellow #10, FD and C
Blue #2 Aluminium Lake, FD and C Green #3, gelatin-NF, propylene glycol, shellac
and titanium dioxide.
12 Clinical Pharmacology
12.1 Mechanism of Action
Omeprazole belongs to a class of antisecretory compounds, the
substituted benzimidazoles, that suppress gastric acid secretion by specific
inhibition of the H
+/K
+ ATPase
enzyme system at the secretory surface of the gastric parietal cell. Because
this enzyme system is regarded as the acid (proton) pump within the gastric
mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in
that it blocks the final step of acid production. This effect is dose-related
and leads to inhibition of both basal and stimulated acid secretion irrespective
of the stimulus. Animal studies indicate that after rapid disappearance from
plasma, omeprazole can be found within the gastric mucosa for a day or
more.
12.2 Pharmacodynamics
Antisecretory Activity
After oral administration, the onset of the antisecretory effect of
omeprazole occurs within one hour, with the maximum effect occurring within two
hours. Inhibition of secretion is about 50% of maximum at 24 hours and the
duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts
far longer than would be expected from the very short (less than one hour)
plasma half-life, apparently due to prolonged binding to the parietal H
+/K
+ ATPase enzyme. When the drug is
discontinued, secretory activity returns gradually, over 3 to 5 days. The
inhibitory effect of omeprazole on acid secretion increases with repeated
once-daily dosing, reaching a plateau after four days.
Results from numerous studies of the antisecretory effect of multiple doses
of 20 mg and 40 mg of omeprazole in normal volunteers and patients are shown
below. The “max” value represents determinations at a time of maximum effect (2
to 6 hours after dosing), while “min” values are those 24 hours after the last
dose of omeprazole.
Table 1 Range of Mean Values from Multiple Studies of the Mean
Antisecretory Effects of Omeprazole After Multiple Daily Dosing
*Single Studies
|
|
Omeprazole |
Omeprazole |
| Parameter |
20 mg |
40 mg |
| % Decrease in Basal Acid Output |
Max
78*
|
Min
58-80
|
Max
94*
|
Min
80-93
|
| % Decrease in Peak Acid Output |
79* |
50-59 |
88* |
62-68 |
| % Decrease in 24-hr. Intragastric Acidity |
|
80-97 |
|
92-94 |
Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg
have produced 100% inhibition of 24-hour intragastric acidity in some
patients.
Serum Gastrin Effects
In studies involving more than 200 patients, serum gastrin levels increased
during the first 1 to 2 weeks of once-daily administration of therapeutic doses
of omeprazole in parallel with inhibition of acid secretion. No further increase
in serum gastrin occurred with continued treatment. In comparison with histamine
H
2-receptor antagonists, the median increases produced by
20 mg doses of omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold
increase). Gastrin values returned to pretreatment levels, usually within 1 to 2
weeks after discontinuation of therapy.
Enterochromaffin-like (ECL) Cell
Effects
Human gastric biopsy specimens have been obtained from more than 3000
patients treated with omeprazole in long-term clinical trials. The incidence of
ECL cell hyperplasia in these studies increased with time; however, no case of
ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients.
[
See Clinical Pharmacology (12)]
However, these studies are of insufficient duration and size to rule out the
possible influence of long-term administration of omeprazole on the development
of any premalignant or malignant conditions.
Other Effects
Systemic effects of omeprazole in the CNS, cardiovascular and respiratory
systems have not been found to date. Omeprazole, given in oral doses of 30 or 40
mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism,
or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone,
prolactin, cholecystokinin or secretin.
No effect on gastric emptying of the solid and liquid components of a test
meal was demonstrated after a single dose of omeprazole 90 mg. In healthy
subjects, a single I.V. dose of omeprazole (0.35 mg/kg) had no effect on
intrinsic factor secretion. No systematic dose-dependent effect has been
observed on basal or stimulated pepsin output in humans.
However, when intragastric pH is maintained at 4.0 or above, basal pepsin
output is low, and pepsin activity is decreased.
As do other agents that elevate intragastric pH, omeprazole administered for
14 days in healthy subjects produced a significant increase in the intragastric
concentrations of viable bacteria. The pattern of the bacterial species was
unchanged from that commonly found in saliva. All changes resolved within three
days of stopping treatment.
The course of Barrett's esophagus in 106 patients was evaluated in a U.S.
double-blind controlled study of omeprazole delayed-release capsules USP 40 mg
twice daily for 12 months followed by 20 mg twice daily for 12 months or
ranitidine 300 mg twice daily for 24 months. No clinically significant impact on
Barrett's mucosa by antisecretory therapy was observed. Although neosquamous
epithelium developed during antisecretory therapy, complete elimination of
Barrett's mucosa was not achieved. No significant difference was observed
between treatment groups in development of dysplasia in Barrett's mucosa and no
patient developed esophageal carcinoma during treatment. No significant
differences between treatment groups were observed in development of ECL cell
hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon
polyps exceeding 3 mm in diameter [
See Clinical Pharmacology
(12)].
12.3 Pharmacokinetics
Absorption
Omeprazole delayed-release capsules USP contain an enteric-coated granule
formulation of omeprazole (because omeprazole is acid-labile), so that
absorption of omeprazole begins only after the granules leave the stomach.
Absorption is rapid, with peak plasma levels of omeprazole occurring within 0.5
to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately
proportional to doses up to 40 mg, but because of a saturable first-pass effect,
a greater than linear response in peak plasma concentration and AUC occurs with
doses greater than 40 mg. Absolute bioavailability (compared with intravenous
administration) is about 30 to 40% at doses of 20 to 40 mg, due in large part to
presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1
hour, and the total body clearance is 500 to 600 mL/min.
The bioavailability of omeprazole increases slightly upon repeated
administration of omeprazole delayed-release capsules USP.
Omeprazole delayed-release capsule USP 40 mg was bioequivalent when
administered with and without applesauce. However, omeprazole delayed-release
capsule USP 20 mg was not bioequivalent when administered with and without
applesauce. When administered with applesauce, a mean 25% reduction in C
max was observed without a significant change in AUC for
omeprazole delayed-release capsule USP 20 mg. The clinical relevance of this
finding is unknown.
Distribution
Protein binding is approximately 95%.
Metabolism
Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme
system.
Excretion
Following single dose oral administration of a buffered solution of
omeprazole, little if any unchanged drug was excreted in urine. The majority of
the dose (about 77%) was eliminated in urine as at least six metabolites. Two
were identified as hydroxyomeprazole and the corresponding carboxylic acid. The
remainder of the dose was recoverable in feces. This implies a significant
biliary excretion of the metabolites of omeprazole. Three metabolites have been
identified in plasma — the sulfide and sulfone derivatives of omeprazole, and
hydroxyomeprazole. These metabolites have very little or no antisecretory
activity.
Combination Therapy with Antimicrobials
Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg
every 8 hours to healthy adult male subjects. The steady state plasma
concentrations of omeprazole were increased (C
max,
AUC
0-24, and T
1/2 increases of
30%, 89% and 34% respectively) by the concomitant administration of
clarithromycin. The observed increases in omeprazole plasma concentration were
associated with the following pharmacological effects. The mean 24-hour gastric
pH value was 5.2 when omeprazole was administered alone and 5.7 when
co-administered with clarithromycin.
The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were
increased by the concomitant administration of omeprazole. For clarithromycin,
the mean C
max was 10% greater, the mean C
min was 27% greater, and the mean AUC
0-8
was 15% greater when clarithromycin was administered with omeprazole than when
clarithromycin was administered alone. Similar results were seen for
14-hydroxy-clarithromycin, the mean C
max was 45% greater,
the mean C
min was 57% greater, and the mean AUC
0-8 was 45% greater. Clarithromycin concentrations in the
gastric tissue and mucus were also increased by concomitant administration of
omeprazole.
Table 2
1Mean ± SD (μg/g)
|
| Clarithromycin Tissue Concentrations
2 hours after Dose
1
|
| Tissue |
Clarithromycin |
Clarithromycin + Omeprazole |
| Antrum |
10.48 ± 2.01 (n = 5) |
19.96 ± 4.71 (n = 5) |
| Fundus |
20.81 ± 7.64 (n = 5) |
24.25 ± 6.37 (n = 5) |
| Mucus |
4.15 ± 7.74 (n = 4) |
39.29 ± 32.79 (n = 4) |
Special Populations
Geriatric Population
The elimination rate of omeprazole was somewhat decreased in the elderly, and
bioavailability was increased. Omeprazole was 76% bioavailable when a single 40
mg oral dose of omeprazole (buffered solution) was administered to healthy
elderly volunteers, versus 58% in young volunteers given the same dose. Nearly
70% of the dose was recovered in urine as metabolites of omeprazole and no
unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min
(about half that of young volunteers) and its plasma half-life averaged one
hour, about twice that of young healthy volunteers.
Pediatric Use
The pharmacokinetics of omeprazole have been investigated in pediatric
patients 2 to 16 years of age:
Table 3 Pharmacokinetic Parameters of Omeprazole Following Single and
Repeated Oral Administration in Pediatric Populations Compared with
Adults
Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg.
|
†Data from single and repeated dose studies
|
‡Data from a single and repeated dose study
|
Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules
|
| Single or |
Children
†
|
Children
†
|
Adults
‡
|
| Repeated |
≤ 20 kg |
> 20 kg |
(mean |
| Oral Dosing |
2 to 5 years |
6 to 16 |
76 kg) |
| /Parameter |
10 mg |
years |
23 to 29 |
|
|
20 mg |
years |
|
|
|
(n=12) |
| Single Dosing |
|
| C
max *
|
288 |
495 |
668 |
| (ng/mL) |
(n=10) |
(n=49) |
|
| AUC* |
511 |
1140 |
1220 |
| (ng h/mL) |
(n=7) |
(n=32) |
|
| Repeated Dosing |
|
| C
max *
|
539 |
851 |
1458 |
| (ng/mL) |
(n=4) |
(n=32) |
|
| AUC* |
1179 |
2276 |
3352 |
| (ng h/mL) |
(n=2) |
(n=23) |
|
Following comparable mg/kg doses of omeprazole, younger children (2 to 5
years of age) have lower AUCs than children 6 to 16 years of age or adults; AUCs
of the latter two groups did not differ. [
See Dosage and
Administration (2)]
Hepatic Impairment
In patients with chronic hepatic disease, the bioavailability increased to
approximately 100% compared with an I.V. dose, reflecting decreased first-pass
effect, and the plasma half-life of the drug increased to nearly 3 hours
compared with the half-life in normals of 0.5 to 1 hour. Plasma clearance
averaged 70 mL/min, compared with a value of 500 to 600 mL/min in normal
subjects. Dose reduction, particularly where maintenance of healing of erosive
esophagitis is indicated, for the hepatically impaired should be
considered.
Renal Impairment
In patients with chronic renal impairment, whose creatinine clearance ranged
between 10 and 62 mL/min/1.73 m
2, the disposition of
omeprazole was very similar to that in healthy volunteers, although there was a
slight increase in bioavailability. Because urinary excretion is a primary route
of excretion of omeprazole metabolites, their elimination slowed in proportion
to the decreased creatinine clearance. No dose reduction is necessary in
patients with renal impairment.
Asian Population
In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in
AUC of approximately four-fold was noted in Asian subjects compared with
Caucasians. Dose reduction, particularly where maintenance of healing of erosive
esophagitis is indicated, for Asian subjects should be considered.
12.4 Microbiology
Omeprazole and clarithromycin dual therapy and omeprazole,
clarithromycin and amoxicillin triple therapy have been shown to be active
against most strains of
Helicobacter pylori in vitro
and in clinical infections as described in the
Indications
and Usage section (1.1).
Helicobacter
Helicobacter pylori-Pretreatment Resistance
Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the
omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3% (41/439) in
omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3).
Amoxicillin pretreatment susceptible isolates (≤ 0.25 μg/mL) were found in
99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin
triple therapy studies (1, 2, and 3). Amoxicillin pretreatment minimum
inhibitory concentrations (MICs) > 0.25 μg/mL occurred in 0.7% (3/439) of the
patients, all of whom were in the clarithromycin and amoxicillin study arm. One
patient had an unconfirmed pretreatment amoxicillin minimum inhibitory
concentration (MIC) of > 256 μg/mL by Etest
®.
Table 4 Clarithromycin Susceptibility Test Results and
Clinical/Bacteriological Outcomes
aIncludes only patients with pretreatment clarithromycin susceptibility test results
|
bSusceptible (S) MIC ≤ 0.25 μg/mL, Intermediate (I) MIC 0.5 – 1.0 μg/mL, Resistant (R) MIC ≥ 2 μg/mL
|
| Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes
a
|
| Clarithromycin Pretreatment Results |
Clarithromycin Post-treatment Results |
|
|
H. pylori negative – eradicated
|
H. pylori positive – not eradicated
|
| Post-treatment susceptibility results |
| S
b
|
I
b
|
R
b
|
No MIC |
| Dual Therapy – (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed by omeprazole 20 mg once daily for another 14 days) (Studies 4, 5) |
| Susceptible
b
|
108 |
72 |
1 |
|
26 |
9 |
| Intermediate
b
|
1 |
|
|
|
1 |
|
| Resistant
b
|
4 |
|
|
|
4 |
|
| Triple Therapy – (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice daily for 10 days – Studies 1, 2, 3; followed by omeprazole 20 mg once daily for another 18 days – Studies 1, 2) |
| Susceptible
b
|
171 |
153 |
7 |
|
3 |
8 |
| Intermediate
b
|
|
|
|
|
|
|
| Resistant
b
|
14 |
4 |
1 |
|
6 |
3 |
Patients not eradicated of
H. pylori following
omeprazole/clarithromycin/amoxicillin triple therapy or
omeprazole/clarithromycin dual therapy will likely have clarithromycin resistant
H. pylori isolates. Therefore, clarithromycin
susceptibility testing should be done, if possible. Patients with clarithromycin
resistant
H. pylori should not be treated with any of
the following: omeprazole/clarithromycin dual therapy,
omeprazole/clarithromycin/amoxicillin triple therapy, or other regimens which
include clarithromycin as the sole antimicrobial agent.
Amoxicillin Susceptibility Test Results and
Clinical/Bacteriological Outcomes
In the triple therapy clinical trials, 84.9% (157/185) of the patients in the
omeprazole/clarithromycin/amoxicillin treatment group who had pretreatment
amoxicillin susceptible MICs (≤ 0.25 μg/mL) were eradicated of
H. pylori and 15.1% (28/185) failed therapy. Of the 28
patients who failed triple therapy, 11 had no post-treatment susceptibility test
results and 17 had post-treatment
H. pylori isolates
with amoxicillin susceptible MICs. Eleven of the patients who failed triple
therapy also had post-treatment
H. pylori isolates
with clarithromycin resistant MICs.
Susceptibility Test for Helicobacter
pylori
The reference methodology for susceptibility testing of
H. pylori is agar dilution MICs
1.
One to three microliters of an inoculum equivalent to a No. 2 McFarland standard
(1 x 10
7 to 1 x 10
8 CFU/mL for
H. pylori) are inoculated directly onto freshly
prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged
defibrinated sheep blood (≥ 2 weeks old). The agar dilution plates are incubated
at 35°C in a microaerobic environment produced by a gas generating system
suitable for campylobacters. After 3 days of incubation, the MICs are recorded
as the lowest concentration of antimicrobial agent required to inhibit growth of
the organism. The clarithromycin and amoxicillin MIC values should be
interpreted according to the following criteria:
Table 5
a These are tentative breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative methods.
|
b There were not enough organisms with MICs > 0.25 μg/mL to determine a resistance breakpoint.
|
| Clarithromycin MIC (μg/mL)
a
|
Interpretation |
| ≤ 0.25 |
Susceptible (S) |
| 0.5 |
Intermediate (I) |
| > 1.0 |
Resistant (R)
|
| Amoxicillin MIC (μg/mL)
a,b
|
Interpretation |
| ≤0.25 |
Susceptible (S) |
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:
aThese are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.
|
| Microorganism |
Antimicrobial Agent |
MIC (μg/mL)
a
|
|
H. pylori ATCC 43504
|
Clarithromycin |
0.016- 0.12 (μg/mL) |
|
H. pylori ATCC 43504
|
Amoxicillin |
0.016- 0.12 (μg/mL) |
Effects on Gastrointestinal Microbial
Ecology
Decreased gastric acidity due to any means including proton pump inhibitors,
increases gastric counts of bacteria normally present in the gastrointestinal
tract. Treatment with proton pump inhibitors may lead to slightly increased risk
of gastrointestinal infections such as
Salmonella and
Campylobacter.
13 Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
In two 24-month carcinogenicity studies in rats, omeprazole at
daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.7 to 57 times a
human dose of 20 mg/day, as expressed on a body surface area basis) produced
gastric ECL cell carcinoids in a dose-related manner in both male and female
rats; the incidence of this effect was markedly higher in female rats, which had
higher blood levels of omeprazole. Gastric carcinoids seldom occur in the
untreated rat. In addition, ECL cell hyperplasia was present in all treated
groups of both sexes. In one of these studies, female rats were treated with
13.8 mg omeprazole/kg/day (about 6 times a human dose of 20 mg/day, based on
body surface area) for one year, and then followed for an additional year
without the drug. No carcinoids were seen in these rats. An increased incidence
of treatment-related ECL cell hyperplasia was observed at the end of one year
(94% treated vs 10% controls). By the second year the difference between treated
and control rats was much smaller (46% vs 26%) but still showed more hyperplasia
in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No
similar tumor was seen in male or female rats treated for two years. For this
strain of rat no similar tumor has been noted historically, but a finding
involving only one tumor is difficult to interpret. In a 52-week toxicity study
in Sprague-Dawley rats, brain astrocytomas were found in a small number of males
that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.2
to 6.5 times the human dose on a body surface area basis). No astrocytomas were
observed in female rats in this study. In a 2-year carcinogenicity study in
Sprague-Dawley rats, no astrocytomas were found in males or females at the high
dose of 140.8 mg/kg/day (about 57 times the human dose on a body surface area
basis). A 78-week mouse carcinogenicity study of omeprazole did not show
increased tumor occurrence, but the study was not conclusive. A 26-week p53
(+/-) transgenic mouse carcinogenicity study was not positive.
Omeprazole was positive for clastogenic effects in an
in
vitro human lymphocyte chromosomal aberration assay, in one of two
in vivo mouse micronucleus tests, and in an
in vivo bone marrow cell chromosomal aberration assay.
Omeprazole was negative in the
in vitro Ames test, an
in vitro mouse lymphoma cell forward mutation assay,
and an
in vivo rat liver DNA damage assay.
Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times the
human dose on a body surface area basis) was found to have no effect on
fertility and reproductive performance.
In 24-month carcinogenicity studies in rats, a dose-related significant
increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in
both male and female animals [
See Warnings and Precautions
(5)] Carcinoid tumors have also been observed in rats
subjected to fundectomy or long-term treatment with other proton pump inhibitors
or high doses of H
2-receptor antagonists.
13.2 Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
Reproductive studies conducted with omeprazole in rats at oral doses up to
138 mg/kg/day (about 56 times the human dose on a body surface area basis) and
in rabbits at doses up to 69 mg/kg/day (about 56 times the human dose on a body
surface area basis) did not disclose any evidence for a teratogenic potential of
omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day
(about 5.5 to 56 times the human dose on a body surface area basis) produced
dose-related increases in embryo-lethality, fetal resorptions, and pregnancy
disruptions. In rats, dose-related embryo/fetal toxicity and postnatal
developmental toxicity were observed in offspring resulting from parents treated
with omeprazole at 13.8 to 138.0 mg/kg/day (about 5.6 to 56 times the human
doses on a body surface area basis).
14 Clinical Studies
14.1 Duodenal Ulcer Disease
Active Duodenal Ulcer— In a multicenter, double-blind, placebo-controlled study of 147 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 2 and 4 weeks was significantly higher with omeprazole
delayed-release capsules USP 20 mg once daily than with placebo (p ≤ 0.01).
Treatment of Active Duodenal Ulcer % of Patients Healed
*(p≤ 0.01)
|
|
Omeprazole delayed-release capsules USP |
Placebo |
|
20 mg a.m |
a.m |
|
(n = 99)
|
(n = 48)
|
| Week 2 |
*41
|
13 |
| Week 4 |
*75
|
27 |
Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated with omeprazole delayed-release capsules USP 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received omeprazole delayed-release capsules USP had complete relief of daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01).
In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 4 weeks was significantly higher with omeprazole delayed-release capsules USP 20 mg once daily than with ranitidine 150 mg b.i.d. (p < 0.01).
Treatment of Active Duodenal Ulcer % of Patients Healed
*(p< 0.01)
|
|
Omeprazole delayed-release capsules USP |
Ranitidine |
|
20 mg a.m |
150 mg twice daily |
|
(n = 145) |
(n = 148)
|
| Week 2 |
42 |
34 |
| Week 4 |
*82
|
63 |
Healing occurred significantly faster in patients treated with omeprazole delayed-release capsules USP than in those treated with ranitidine 150 mg b.i.d. (p < 0.01).
In a foreign multinational randomized, double-blind study of 105 patients with endoscopically documented duodenal ulcer, 20 mg and 40 mg of omeprazole delayed-release capsules USP were compared with 150 mg b.i.d. of ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of omeprazole delayed-release capsules USP were statistically superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of omeprazole delayed-release capsules USP, and at 8 weeks there was no significant difference between any of the active drugs.
Treatment of Active Duodenal Ulcer % of Patients Healed
*(p≤ 0.01)
|
|
Omeprazole delayed-release capsules USP |
Ranitidine |
|
20 mg
(n = 34)
|
40 mg
(n = 36)
|
150 mg twice daily
(n = 35)
|
|
| Week 2 |
*83
|
*83
|
53 |
| Week 4 |
*97
|
*100
|
82 |
| Week 8 |
100 |
100 |
94 |
H. pylori Eradication in Patients with
Duodenal Ulcer Disease
Triple Therapy(Omeprazole delayed-release
capsules USP /clarithromycin/amoxicillin)—
Three U.S., randomized, double-blind clinical studies in patients with
H. pylori infection and duodenal ulcer disease (n = 558)
compared omeprazole delayed-release capsules USP plus clarithromycin plus
amoxicillin with clarithromycin plus amoxicillin. Two studies (1 and 2) were
conducted in patients with an active duodenal ulcer, and the other study (3) was conducted in patients with a history of a duodenal ulcer
in the past 5 years but without an ulcer present at the time of enrollment. The
dose regimen in the studies was omeprazole delayed-release capsules USP 20 mg
twice daily plus clarithromycin 500 mg twice daily plus amoxicillin 1 g twice
daily for 10 days; or clarithromycin 500 mg. twice daily plus amoxicillin 1 g
twice daily for 10 days. In studies 1 and 2, patients who took the omeprazole
regimen also received an additional 18 days of omeprazole delayed-release
capsules USP 20 mg once daily. Endpoints studied were eradication of
H. pylori and duodenal ulcer healing (studies 1 and 2
only).
H. pylori status was determined by
CLOtest
®, histology and culture in all three studies. For
a given patient,
H. pylori was considered eradicated
if at least two of these tests were negative, and none was positive.
The combination of omeprazole plus clarithromycin plus amoxicillin was
effective in eradicating
H. pylori.
Table 6
† Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer within 5 years, study 3) and
H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest
®, histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer.
|
‡ Patients were included in the analysis if they had documented
H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.
|
* (p < 0.05) versus clarithromycin plus amoxicillin.
|
| Per-Protocol and Intent-to-Treat
H. pylori Eradication Rates % of Patients Cured [95% Confidence Interval]
|
|
Omeprazole delayed-release capsules USP +clarithromycin
+amoxicillin
|
Clarithromycin +amoxicillin |
|
Per-Protocol † |
Intent-to-Treat ‡ |
Per-Protocol † |
Intent-to-Treat ‡ |
| Study 1 |
*77 [64, 86]
(n = 64)
|
*69 [57, 79]
(n = 80)
|
43 [31, 56]
(n = 67)
|
37 [27, 48]
(n = 84)
|
| Study 2 |
*78 [67, 88]
(n = 65)
|
*73 [61, 82]
(n = 77)
|
41 [29, 54]
(n = 68)
|
36 [26, 47]
(n = 83)
|
| Study 3 |
*90 [80, 96]
(n = 69)
|
*83 [74, 91]
(n = 84)
|
33 [24, 44]
(n = 93)
|
32 [23, 42]
(n = 99)
|
Dual Therapy (Omeprazole delayed-release
capsules USP /clarithromycin)
Four randomized, double-blind, multi-center studies (4, 5, 6, and 7)
evaluated omeprazole delayed-release capsules USP 40 mg once daily plus
clarithromycin 500 mg three times daily for 14 days, followed by omeprazole
delayed-release capsules USP 20 mg once daily, (Studies 4, 5, and 7) or by
omeprazole delayed-release capsules USP 40 mg once daily (Study 6) for an
additional 14 days in patients with active duodenal ulcer associated with
H. pylori. Studies 4 and 5 were conducted in the U.S. and
Canada and enrolled 242 and 256 patients, respectively
. H.
pylori infection and duodenal ulcer were confirmed in 219 patients in
Study 4 and 228 patients in Study 5. These studies compared the combination
regimen to omeprazole delayed-release capsules USP and clarithromycin
monotherapies. Studies 6 and 7 were conducted in Europe and enrolled 154 and 215
patients, respectively.
H. pylori infection and
duodenal ulcer were confirmed in 148 patients in study 6 and 208 patients in
Study 7. These studies compared the combination regimen with omeprazole
monotherapy. The results for the efficacy analyses for these studies are
described below.
H. pylori eradication was defined as
no positive test (culture or histology) at 4 weeks following the end of
treatment, and two negative tests were required to be considered eradicated of
H. pylori. In the per-protocol analysis, the
following patients were excluded: dropouts, patients with missing
H. pylori tests post-treatment, and patients that were not
assessed for
H. pylori eradication because they were
found to have an ulcer at the end of treatment.
The combination of omeprazole and clarithromycin was effective in eradicating
H. pylori.
Table 7
†Statistically significantly higher than clarithromycin monotherapy (p < 0.05)
|
‡Statistically significantly higher than omeprazole monotherapy (p < 0.05)
|
|
H. pylori Eradication Rates (Per-Protocol Analysis at 4 to 6 Weeks) % of Patients Cured [95% Confidence Interval]
|
|
Omeprazole delayed-release capsules USP+ Clarithromycin |
Omeprazole delayed-release capsules USP |
Clarithromycin |
|
U.S. Studies
|
|
|
|
| Study 4 |
74 [60, 85] †‡
(n = 53)
|
0 [0, 7]
(n = 54)
|
31 [18, 47]
(n = 42)
|
| Study 5 |
64 [51, 76] †‡
(n = 61)
|
0 [0, 6]
(n = 59)
|
39 [24, 55]
(n = 44)
|
|
Non U.S. Studies
|
| Study 6 |
83 [71, 92] ‡
(n = 60)
|
1 [0, 7]
(n = 74)
|
N/A |
| Study 7 |
74 [64, 83] ‡
(n = 86)
|
1 [0, 6]
(n = 90)
|
N/A |
Ulcer healing was not significantly different when clarithromycin was added
to omeprazole therapy compared with omeprazole therapy alone.
The combination of omeprazole and clarithromycin was effective in eradicating
H. pylori and reduced duodenal ulcer
recurrence.
Table 8
#
H. pylori eradication status assessed at same time point as ulcer recurrence
|
†Combined results for omeprazole delayed-release capsules USP+ clarithromycin, omeprazole delayed-release capsules USP, and clarithromycin treatment arms
|
‡Combined results for omeprazole delayed-release capsules USP + clarithromycin and omeprazole delayed-release capsules USP treatment arms
|
*(p≤ 0.01) versus proportion with duodenal ulcer recurrence who were not
H. pylori eradicated
|
| Duodenal Ulcer Recurrence Rates by
H. pylori Eradication Status % of Patients with Ulcer Recurrence
|
|
H. pylori eradicated#
|
H. pylori not eradicated#
|
|
U.S. Studies †
|
|
|
| 6 months post-treatment |
|
| Study 4 |
*35
(n = 49)
|
60
(n = 88)
|
| Study 5 |
*8
(n = 53)
|
60
(n = 106)
|
|
Non U.S. Studies ‡
|
| 6 months post-treatment |
|
| Study 6 |
*5
(n = 43)
|
46
(n = 78)
|
| Study 7 |
*6
(n = 53)
|
43
(n = 107)
|
| 12 months post-treatment |
| Study 6 |
*5
(n = 39)
|
68
(n = 71)
|
14.2 Gastric Ulcer
In a U.S. multicenter, double-blind, study of omeprazole 40 mg
once daily, 20 mg once daily, and placebo in 520 patients with endoscopically
diagnosed gastric ulcer, the following results were obtained.
Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated)
**(p < 0.01) omeprazole delayed-release capsules USP 40 mg or 20 mg versus placebo
+(p < 0.05) omeprazole delayed-release capsules USP 40 mg versus 20 mg
|
|
Omeprazole delayed-release capsules USP 20 mg once daily
(n = 202)
|
Omeprazole delayed-release capsules USP 40 mg once daily
(n = 214)
|
Placebo
(n = 104)
|
| Week 4 |
47.5
**
|
55.6
**
|
30.8 |
| Week 8 |
74.8
**
|
82.7
**,+
|
48.1 |
For the stratified groups of patients with ulcer size less than or equal to 1
cm, no difference in healing rates between 40 mg and 20 mg was detected at
either 4 or 8 weeks. For patients with ulcer size greater than 1 cm, 40 mg was
significantly more effective than 20 mg at 8 weeks.
In a foreign, multinational, double-blind study of 602 patients with
endoscopically diagnosed gastric ulcer, omeprazole 40 mg once daily, 20 mg once
daily, and ranitidine 150 mg twice a day were evaluated.
Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated)
** (p < 0.01) omeprazole delayed-release capsules USP 40 mg versus ranitidine
|
++ (p < 0.01) omeprazole delayed-release capsules USP 40 mg versus 20 mg
|
|
Omeprazole delayed-release capsules USP |
|
Omeprazole delayed-release capsules USP |
|
Ranitidine |
|
20 mg once daily |
|
40 mg once daily |
|
150 twice daily |
|
(n = 200) |
|
(n = 187) |
|
(n = 199) |
| Week 4 |
63.5 |
|
78.1
**,++
|
|
56.3 |
| Week 8 |
81.5 |
|
91.4
**,++
|
|
78.4 |
14.3 Gastroesophageal Reflux Disease (GERD)
Symptomatic GERD
A placebo-controlled study was conducted in Scandinavia to compare the
efficacy of omeprazole 20 mg or 10 mg once daily for up to 4 weeks in the
treatment of heartburn and other symptoms in GERD patients without erosive
esophagitis. Results are shown below.
aDefined as complete resolution of heartburn
|
*(p < 0.005) versus 10 mg
|
†(p < 0.005) versus placebo
|
|
% Successful Symptomatic Outcome
a
|
|
Omeprazole delayed-release capsules USP |
|
Omeprazole delayed-release capsules USP |
|
Placebo |
|
20 mg a.m. |
|
10 mg a.m. |
|
a.m. |
| All patients |
46
*,†
|
|
31† |
|
13 |
|
(n = 205) |
|
(n = 199) |
|
(n = 105) |
| Patients with |
56
*,†
|
|
36
†
|
|
14 |
| confirmed GERD |
(n = 115) |
|
(n = 109) |
|
(n = 59) |
14.4 Erosive Esophagitis
In a U.S. multicenter double-blind placebo controlled study of 20
mg or 40 mg of omeprazole delayed-release capsules USP in patients with symptoms
of GERD and endoscopically diagnosed erosive esophagitis of grade 2 or above,
the percentage healing rates (per protocol) were as follows:
**(p < 0.01) Omeprazole delayed-release capsules USP versus placebo.
|
|
20 mg Omeprazole delayed-release capsules USP |
|
40 mg Omeprazole delayed-release capsules USP |
|
Placebo |
| Week |
(n = 83) |
|
(n = 87) |
|
(n = 43) |
| 4 |
39** |
|
45** |
|
7 |
| 8 |
74** |
|
75** |
|
14 |
In this study, the 40 mg dose was not superior to the 20 mg dose of
omeprazole delayed-release capsules USP in the percentage healing rate. Other
controlled clinical trials have also shown that omeprazole delayed-release
capsules USP is effective in severe GERD. In comparisons with histamine H
2-receptor antagonists in patients with erosive esophagitis,
grade 2 or above, omeprazole delayed-release capsules USP in a dose of 20 mg was
significantly more effective than the active controls. Complete daytime and
nighttime heartburn relief occurred significantly faster (p less than 0.01) in
patients treated with omeprazole delayed-release capsules USP than in those
taking placebo or histamine H
2- receptor antagonists.
In this and five other controlled GERD studies, significantly more patients
taking 20 mg omeprazole (84%) reported complete relief of GERD symptoms than
patients receiving placebo (12%).
Long Term Maintenance Of Healing of Erosive
Esophagitis
In a U.S. double-blind, randomized, multicenter, placebo controlled study,
two dose regimens of omeprazole delayed-release capsules USP were studied in
patients with endoscopically confirmed healed esophagitis. Results to determine
maintenance of healing of erosive esophagitis are shown below.
Life Table Analysis
∗(p < 0.01) omeprazole delayed-release capsules USP 20 mg once daily versus omeprazole delayed-release capsules 20 mg 3 consecutive days per week or placebo.
|
|
|
|
Omeprazole delayed-release capsules USP |
|
|
|
Omeprazole delayed-release capsules USP |
|
20 mg 3 days |
|
|
|
20 mg once daily |
|
per week |
|
Placebo |
|
(n = 138) |
|
(n = 137) |
|
(n = 131) |
| Percent in |
|
|
|
|
|
| endoscopic |
|
|
|
|
|
| remission at |
|
|
|
|
|
| 6 months |
*70
|
|
34 |
|
11 |
|
|
|
|
|
|
In an international multicenter double-blind study, omeprazole
delayed-release capsules USP 20 mg daily and 10 mg daily were compared with
ranitidine 150 mg twice daily in patients with endoscopically confirmed healed
esophagitis. The table below provides the results of this study for maintenance
of healing of erosive esophagitis.
Life Table Analysis
* (p = 0.01) omeprazole delayed-release capsules USP 20 mg once daily versus omeprazole delayed-release capsules USP 10 mg once daily or Ranitidine.
|
‡ (p = 0.03) omeprazole delayed-release capsules USP 10 mg once daily versus Ranitidine.
|
|
Omeprazole delayed-release capsules USP |
|
Omeprazole delayed-release capsules USP |
|
Ranitidine |
|
20 mg once daily |
|
10 mg once daily |
|
150 mg twice daily |
|
(n = 131) |
|
(n = 133) |
|
(n = 128) |
| Percent in |
|
|
|
|
|
| endoscopic |
|
|
|
|
|
| remission at |
|
|
|
|
|
| 12 months |
*77
|
|
‡58
|
|
46 |
In patients who initially had grades 3 or 4 erosive esophagitis, for
maintenance after healing 20 mg daily of omeprazole delayed-release capsules USP
was effective, while 10 mg did not demonstrate effectiveness.
14.5 Pathological Hypersecretory Conditions
In open studies of 136 patients with pathological hypersecretory
conditions, such as Zollinger-Ellison (ZE) syndrome with or without multiple
endocrine adenomas, omeprazole delayed-release capsules USP significantly
inhibited gastric acid secretion and controlled associated symptoms of diarrhea,
anorexia, and pain. Doses ranging from 20 mg every other day to 360 mg per day
maintained basal acid secretion below 10 mEq/hr in patients without prior
gastric surgery, and below 5 mEq/hr in patients with prior gastric surgery.
Initial doses were titrated to the individual patient need, and adjustments
were necessary with time in some patients [
See Dosage and
Administration (2)] omeprazole delayed-release
capsules USP was well tolerated at these high dose levels for prolonged periods
(greater than 5 years in some patients). In most ZE patients, serum gastrin levels were
not modified by omeprazole delayed-release capsules USP. However, in some
patients serum gastrin increased to levels greater than those present prior to
initiation of omeprazole therapy. At least 11 patients with ZE syndrome on
long-term treatment with omeprazole delayed-release capsules USP developed
gastric carcinoids. These findings are believed to be a manifestation of the
underlying condition, which is known to be associated with such tumors, rather
than the result of the administration of omeprazole delayed-release capsules USP
. [
See Adverse Reactions (6)]
14.6 Pediatric GERD
Symptomatic GERD
The effectiveness of omeprazole delayed-release capsules USP for the
treatment of nonerosive GERD in pediatric patients 1 to 16 years of age is based
in part on data obtained from 125 pediatric patients in two uncontrolled Phase
III studies. [
See Use in Specific Populations (8.4)]
The first study enrolled 12 pediatric patients 1 to 2 years of age with a
history of clinically diagnosed GERD. Patients were administered a single dose
of omeprazole (0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg) for 8 weeks as an open
capsule in 8.4% sodium bicarbonate solution. Seventy-five percent (9/12) of the
patients had vomiting/regurgitation episodes decreased from baseline by at least
50%.
The second study enrolled 113 pediatric patients 2 to 16 years of age with a
history of symptoms suggestive of nonerosive GERD. Patients were administered a
single dose of omeprazole (10 mg or 20 mg, based on body weight) for 4 weeks
either as an intact capsule or as an open capsule in applesauce. Successful
response was defined as no moderate or severe episodes of either pain-related
symptoms or vomiting/regurgitation during the last 4 days of treatment. Results
showed success rates of 60% (9/15; 10 mg omeprazole) and 59% (58/98; 20 mg
omeprazole), respectively.
Healing of Erosive Esophagitis
In an uncontrolled, open-label dose-titration study, healing of erosive
esophagitis in pediatric patients 1 to 16 years of age required doses that
ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were initiated at 0.7
mg/kg/day. Doses were increased in increments of 0.7 mg/kg/day (if
intraesophageal pH showed a pH of less than 4 for less than 6% of a 24-hour study).
After titration, patients remained on treatment for 3 months. Forty-four percent
of the patients were healed on a dose of 0.7 mg/kg body weight; most of the
remaining patients were healed with 1.4 mg/kg after an additional 3 months'
treatment. Erosive esophagitis was healed in 51 of 57 (90%) children who
completed the first course of treatment in the healing phase of the study. In
addition, after 3 months of treatment, 33% of the children had no overall
symptoms, 57% had mild reflux symptoms, and 40% had less frequent
regurgitation/vomiting.
Maintenance of Healing of Erosive
Esophagitis
In an uncontrolled, open-label study of maintenance of healing of erosive
esophagitis in 46 pediatric patients, 54% of patients required half the healing
dose. The remaining patients increased the healing dose (0.7 to a maximum of 2.8
mg/kg/day) either for the entire maintenance period, or returned to half the
dose before completion. Of the 46 patients who entered the maintenance phase, 19
(41%) had no relapse. In addition, maintenance therapy in erosive esophagitis
patients resulted in 63% of patients having no overall symptoms.
15 References
- National Committee for Clinical Laboratory Standards.
Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria That Grow Aerobically—Fifth Edition. Approved Standard NCCLS
Document M7-A5, Vol, 20, No. 2, NCCLS, Wayne, PA, January 2000.
16 How Supplied/storage And Handling
Omeprazole Delayed-release Capsules USP, 40 mg, are opaque, hard gelatin,
dark green and light green colored capsules, imprinted “Andrx 640” on cap and
“40 mg” on the body. They are supplied as follows:
NDC 0179-0016-70 30 Capsule in 1 Box, UNIT-DOSE
Storage
Store Omeprazole Delayed-release Capsules USP in a tight container protected from light and moisture. Store at controlled room temperature, 20° - 25°C (68° – 77°F). [See USP.]
17 Patient Counseling Information
Omeprazole delayed-release capsules USP should be taken before eating. Patients should be informed that the omeprazole delayed-release capsule USP should be swallowed whole.
For patients who have difficulty swallowing capsules, the contents of a omeprazole delayed-release capsule USP can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the pellets inside the capsule should be carefully emptied on the applesauce. The pellets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or crushed. The pellets/applesauce mixture should not be stored for future use.
Manufactured by:
Watson Laboratories, Inc.
Corona, CA 92880. USA
Distributed by:
Watson Pharma, Inc.
Repackaged by:
Kaiser Foundation Hospitals
Livermore, CA 94551
Package Label - Principal Display Panel
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